Antiviral drug screen identifies DNA-damage response inhibitor as potent blocker of SARS-CoV-2 replication.

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.

Folate receptor targeted bufalin/ß-cyclodextrin supramolecular inclusion complex for enhanced solubility and anti-tumor efficiency of bufalin.

Bufalin (BF), a traditional Chinese medicine, exhibited inhibitory activities against a broad spectrum of tumor cells. The present study elaborates that bufalin was successfully encapsulated into the cavity of ß-cyclodextrin (ß-CD), which was determined by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The best reaction mole ratio of BF/ß-CD was 1:5. The solubilities of bufalin in water and phosphate buffer solution (pH=7.4) were increased up to 24 and 34 times after encapsulated into the cavity of ß-CD respectively. The inclusion efficiency (IE) and drug loading (DL) of bufalin in the inclusion complex were (94.22±0.85)% and (14.11±0.20)%, respectively. Then ß-CD conjugated with folic acid (FA) were further prepared and employed to improve the anti-tumor efficacy of inclusion complex. The in vitro dissolution and solubility study showed better values of inclusion complex and FA targeted inclusion complex than that of pure BF. Cytotoxicity experiments by using HCT116 cell line revealed that the antitumor efficiency of bufalin were enhanced more than two folds in the presence of ß-CD and folate conjugated ß-CD (FA-PEI-ß-CD), which demonstrated the potential application of ß-CD (FA-PEI-ß-CD) as delivery vehicles of bufalin for antitumor therapy.

Antitumor Effects of Sorbus aucuparia L. Extract Highly Saturated with Anthocyans and Their Mechanisms.

The effects of Fructus Sorbi aucupariae extract, originally saturated with anthocyans, on the development of Lewis lung carcinoma and B-16 melanoma in C57Bl/6 mice and the efficiency of cyclophosphamide treatment were studied. Antitumor activity of the extract and potentiation of the antimetastatic activity of the cytostatic were demonstrated. Studies on melanoma B-16 model revealed an increase in the counts of stromal progenitor cells in the tumor node and their accelerated maturation after treatment with the extract. No effects towards the tumor stem and committed cells were detected.

Pitfalls in the diagnostic evaluation of subacute combined degeneration.

We report a case of a 43-year-old man presenting with a 2-week history of painless ascending sensory disturbances, suspected to be suffering from acute inflammatory polyneuropathy. On clinical examination, deep tendon reflexes were preserved and muscle strength was 5/5 everywhere. Gait was ataxic with positive Romberg test. Lumbar puncture was normal and electroneurography demonstrated demyelination. With spinal cord involvement centred on the posterior tracts on MRI, differential diagnosis focused on cobalamin deficiency. Initial laboratory work up showed nearly normal holotranscobalamin (43 pmol/L, normal>50) suggesting no vitamin B12 deficiency. Surprisingly, further testing including methylmalonic acid (3732 nmol/L, normal<271) and homocysteine (48.5 µmol/L, normal<10) showed an impairment of vitamin B12-dependent metabolism leading to the diagnosis of subacute combined degeneration. Only after repeated history taking did the patient remember having taken tablets containing cobalamin for 3 days before hospitalisation. In case of B12 deficiency, holotranscobalamin can rapidly normalise during supplementation, whereas methylmalonic acid and homocysteine might help to detect B12 deficiency in patients who recently started supplementation.

Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility.

INTRODUCTION: Neutrophil extracellular traps (NETs) have recently been implicated in a number of autoimmune conditions, including rheumatoid arthritis (RA). We examined the underlying signaling pathways triggering enhanced NETosis in RA and ascertained whether the products of NETosis had diagnostic implications or usefulness. METHODS: Neutrophils were isolated from RA patients with active disease and from controls. Spontaneous NET formation from RA and control neutrophils was assessed in vitro with microscopy and enzyme-linked immunosorbent assay (ELISA) for NETosis-derived products. The analysis of the signal-transduction cascade included reactive oxygen species (ROS) production, myeloperoxidase (MPO), neutrophil elastase (NE), peptidyl arginine deiminase 4 (PAD4), and citrullinated histone 3 (citH3). NET formation was studied in response to serum and synovial fluid and immunoglobulin G (IgG) depleted and reconstituted serum. Serum was analyzed for NETosis-derived products, for which receiver operator characteristic (ROC) curves were calculated. RESULTS: Neutrophils from RA cases exhibited increased spontaneous NET formation in vitro, associated with elevated ROS production, enhanced NE and MPO expression, nuclear translocation of PAD4, PAD4-mediated citrullination of H3, and altered nuclear morphology. NET formation in both anti-citrullinated peptide antibody (ACPA)-positive and -negative RA was abolished by IgG depletion, but restored only with ACPA-positive IgG. NETosis-derived products in RA serum demonstrated diagnostic potential, the ROC area under the curve for cell-free nucleosomes being >97%, with a sensitivity of 91% and a specificity of 92%. No significant difference was observed between ACPA-positive and -negative cases. CONCLUSIONS: Signaling elements associated with the extrusion of NETs are significantly enhanced to promote NETosis in RA compared with healthy controls. NETosis depended on the presence of ACPA in ACPA-positive RA serum. The quantitation of NETosis-derived products, such as cell-free nucleosomes in serum, may be a useful complementary tool to discriminate between healthy controls and RA cases.

[Radiotherapy-associated morbidity and mortality in rectal surgery]. / Strahlentherapieassoziierte Morbidität und Mortalität in der Rektumchirurgie.

The treatment of rectal cancer has evolved significantly in recent decades. Both modern radiotherapy treatment concepts and surgical techniques have been able to improve oncological as well as functional outcomes for rectal cancer patients. Large-scale, multicenter, randomized trials have been able to demonstrate the benefits of neoadjuvant treatment over adjuvant radiotherapy. In addition, local tumor control is improved by neoadjuvant irradiation. Conversely, patients receiving a total mesorectal excision showed no survival advantage following irradiation vs. only surgically resected patients. In addition, radiation therapy is associated with a certain morbidity and mortality. This paper summarizes the available evidence regarding postoperative morbidity, mortality, and long-term chronic effects of neoadjuvant radiotherapy.

Biogeochemical processes controlling the mobility of major ions and trace metals in aquitard sediments beneath an oil sand tailing pond: laboratory studies and reactive transport modeling.

Increased production and expansion of the oil sand industry in Alberta are of great benefit to the economy, but they carry major environmental challenges. The volume of fluid fine tailings requiring storage is 840×10(6) m(3) and growing, making it imperative that we better understand the fate and transport of oil sand process-affected water (OSPW) seepage from these facilities. Accordingly, the current study seeks to characterize both a) the potential for major ion and trace element release, and b) the principal biogeochemical processes involved, as tailing pond OSPW infiltrates into, and interacts with, underlying glacial till sediments prior to reaching down gradient aquifers or surface waters. Objectives were addressed through a series of aqueous and solid phase experiments, including radial diffusion cells, an isotope analysis, X-ray diffraction, and sequential extractions. The diffusion cells were also simulated in a reactive transport framework to elucidate key reaction processes. The experiments indicate that the ingress and interaction of OSPW with the glacial till sediment-pore water system will result in: a mitigation of ingressing Na (retardation), displacement and then limited precipitation of exchangeable Ca and Mg (as carbonates), sulfate reduction and subsequent precipitation of the produced sulfides, as well as biodegradation of organic carbon. High concentrations of ingressing Cl (~375 mg L(-1)) and Na (~575 mg L(-1)) (even though the latter is delayed, or retarded) are expected to migrate through the till and into the underlying sand channel. Trace element mobility was influenced by ion exchange, oxidation-reduction, and mineral phase reactions including reductive dissolution of metal oxyhydroxides - in accordance with previous observations within sandy aquifer settings. Furthermore, although several trace elements showed the potential for release (Al, B, Ba, Cd, Mn, Pb, Si, Sr), large-scale mobilization is not supported. Thus, the present results suggest that in addition to the commonly cited naphthenic acids, remediation of OSPW-impacted groundwater will need to address high concentrations of major ions contributing to salinization.

Enhanced uridine bioavailability following administration of a triacetyluridine-rich nutritional supplement.

BACKGROUND: Uridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. Historically, the use of uridine as a therapeutic agent has been limited by poor bioavailability. A food supplement containing nucleosides, NucleomaxX®, has been reported to raise plasma uridine to supraphysiologic levels. METHODOLOGY/PRINCIPAL FINDINGS: Single- and multi-dose PK studies following NucleomaxX® were compared to single-dose PK studies of equimolar doses of pure uridine in healthy human volunteers. Product analysis documented that more than 90% of the nucleoside component of NucleomaxX® is in the form of triacetyluridine (TAU). Single and repeated dosing with NucleomaxX® resulted in peak plasma uridine concentrations 1-2 hours later of 150.9 ± 39.3 µM and 161.4 ± 31.5 µM, respectively, levels known to ameliorate mitochondrial toxicity in vitro. C(max) and AUC were four-fold higher after a single dose of NucleomaxX® than after uridine. No adverse effects of either treatment were observed. CONCLUSIONS/SIGNIFICANCE: NucleomaxX®, containing predominantly TAU, has significantly greater bioavailability than pure uridine in human subjects and may be useful in the management of mitochondrial toxicity.

Geochemical interactions between process-affected water from oil sands tailings ponds and North Alberta surficial sediments.

In Northern Alberta, the placement of out-of-pit oil sands tailings ponds atop natural buried sand channels is becoming increasingly common. Preliminary modeling of such a site suggests that process-affected (PA) pond water will infiltrate through the underlying clay till aquitard, reaching the sand channel. However, the impact of seepage upon native sediments and groundwater resources is not known. The goal of this study is to investigate the role of adsorption and ion exchange reactions in the clay till and their effect on the attenuation or release of inorganic species. This was evaluated using batch sorption experiments (traditional and a recent modification using less disturbed sediment samples) and geochemical modeling with PHREEQC. The results show that clay till sediments have the capacity to mitigate the high concentrations of ingressing sodium (600 mg L(-1)), with linear sorption partitioning coefficients (K(d)) of 0.45 L kg(-1). Ion exchange theory was required to account for all other cation behaviour, precluding the calculation of such coefficients for other species. Qualitative evidence suggests that chloride will behave conservatively, with high concentrations remaining in solution (375 mg L(-1)). As a whole, system behaviour was found to be controlled by a combination of competitive ion exchange, dissolution and precipitation reactions. Observations, supported by PHREEQC simulations, suggest that the influx of PA water will induce the dissolution of pre-existing sulphate salts. Sodium present in the process-affected water will exchange with sediment-bound calcium and magnesium, increasing the divalent ions' pore fluid concentrations, and leading to the precipitation of a calcium-magnesium carbonate mineral phase. Thus, in similar tailings pond settings, particularly if the glacial till coverage is thin or altogether absent, it is reasonable to expect that high concentrations of sodium and chloride will remain in solution, while sulphate concentrations will exceed those of the ingressing plume (150 mg L(-1)).

Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.

OBJECTIVE: Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. METHODS: Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. RESULTS: Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. CONCLUSIONS: Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.

Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine.

Stavudine is a hepatotoxic antiretroviral nucleoside analogue that also inhibits the replication of mitochondrial DNA (mtDNA). To elucidate the mechanism and consequences of mtDNA depletion, we treated HepG2 cells with stavudine and either redoxal, an inhibitor of de novo pyrimidine synthesis, or uridine, from which pyrimidine pools are salvaged. Compared with treatment with stavudine alone, co-treatment with redoxal accelerated mtDNA depletion, impaired cell division, and activated caspase 3. These adverse effects were completely abrogated by uridine. Intracellular ATP levels were unaffected. Transcriptosome profiling demonstrated that redoxal and stavudine acted synergistically to induce CDKN2A and p21, indicating cell cycle arrest in G1, as well as genes involved in intrinsic and extrinsic apoptosis. Moreover, redoxal and stavudine showed synergistic interaction in the up-regulation of transcripts encoded by mtDNA and the induction of nuclear transcripts participating in energy metabolism, mitochondrial biogenesis, oxidative stress, and DNA repair. Genes involved in nucleotide metabolism were also synergistically up-regulated by both agents; this effect was completely antagonized by uridine. Thus, pyrimidine depletion sensitizes cells to stavudine-mediated mtDNA depletion and enhances secondary cell toxicity. Our results indicate that drugs that diminish pyrimidine pools should be avoided in stavudine-treated human immunodeficiency virus patients. Uridine supplementation reverses this toxicity and, because of its good tolerability, has potential clinical value for the treatment of side effects associated with pyrimidine depletion.

IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state.

IL-17-producing Th (Th17) comprise a distinct lineage of pro-inflammatory Th that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGFbeta) induces naive CD4+ T cells to generate Th17, which also requires expression of the IL-6/TGFbeta target RORgammat. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of RORgammat by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases.

Uridine supplementation for the treatment of antiretroviral therapy-associated lipoatrophy: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Highly active antiretroviral therapy (HAART) is associated with loss of subcutaneous fat (lipoatrophy) presumably due to mitochondrial toxicity of nucleoside reverse transcriptase inhibitors. In vitro, uridine abrogates thymidine analogue-induced toxicity in adipocytes. METHODS: A total of 20 patients with HAART-associated lipoatrophy were randomized to receive either a dietary uridine supplement (36 g three times a day for 10 consecutive days/month) or placebo, for 3 months. Body composition was measured using dual energy X-ray absorptiometry, magnetic resonance imaging and proton spectroscopy. Data are mean +/- standard error of mean. RESULTS: The mean increases in limb fat (880 +/- 140 versus 230 +/- 270 g; P < 0.05), intra-abdominal fat (210 +/- 80 versus -80 +/- 70 cm3; P < 0.05) and total body fat (1920 +/- 240 versus 240 +/- 520 g; P < 0.01) were significantly greater in the uridine than in the placebo group. Within the uridine group, the changes from baseline to 3 months were statistically significant in total limb fat (P < 0.001), intra-abdominal fat (P < 0.05) and total body fat (P < 0.001). The proportion of limb fat to total fat increased from 18% to 25% (P < 0.05) in the uridine group. Liver fat content and lean body mass remained unchanged in both groups. High-density lipoprotein-cholesterol concentrations decreased in the uridine and increased in the placebo group, whereas fasting serum insulin concentrations did not change. Uridine supplementation was well tolerated and the virological effect of HAART was not affected. CONCLUSION: Uridine supplementation significantly and predominantly increased subcutaneous fat mass in lipoatrophic HIV-infected patients during unchanged HAART.

Uridine supplementation antagonizes zalcitabine-induced microvesicular steatohepatitis in mice.

UNLABELLED: Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. CONCLUSION: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.

Seasonal profiles of sulphur, phosphorus, and potassium in Norway spruce wood.

Seasonal profiles of sulphur, phosphorus, and potassium content in the wood of trees have been established for the first time. This became possible by using a novel laser ablation system coupled to HR-ICP-MS for measuring these elements in Norway spruce drill cores. This technique combines excellent spatial resolution with superior detection power, and makes it possible to measure low element concentrations even in relatively narrow annual rings. Despite its low quantity in wood, sulphur is an important macronutrient for plants and seems to display seasonal variations of its concentration, which correspond to actual theories of sulphur metabolism in plants. A similar seasonal pattern was also found for phosphorus, another crucial element in tree nutrition. This was unexpected, because it was previously assumed that the distribution of phosphorus remains constant throughout the year. Potassium, the third element measured, seems to be especially accumulated in the latewood. The profiles presented in this article suggest a seasonal variation, revealing some new aspects of Norway spruce (PICEA ABIES) metabolism.

Uridine abrogates mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors in HepG2 cells.

OBJECTIVE: To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). METHODS: Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. RESULTS: HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 microM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 microM of stavudine and protected HepG2-cells exposed to 7 microM of zidovudine + 8 microM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 microM of didanosine (a purine analogue). CONCLUSIONS: The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.

Chronic alpha-tocopherol supplementation in rats does not ameliorate either chronic or acute alcohol-induced changes in muscle protein metabolism.

Chronic alcohol muscle disease is characterized by reduced skeletal muscle mass precipitated by acute reduction in protein synthesis. The pathogenic mechanisms remain obscure, but several lines of evidence suggest that increased oxidative stress occurs in muscle in response to alcohol and this may be associated with impaired alpha-tocopherol status. Potentially, this implies a therapeutic role for alpha-tocopherol, especially as we have shown that supplemental alpha-tocopherol may increase the rate of protein synthesis in normal rats [Reilly, Patel, Peters and Preedy (2000) J. Nutr. 130, 3045-3049]. We investigated the therapeutic effect of alpha-tocopherol on plantaris muscle protein synthesis in rats treated either acutely, chronically or chronically+acutely with ethanol. Protein synthesis rates were measured with a flooding dose of L-[4-(3)H]phenylalanine. Protein, RNA and DNA contents were determined by standard laboratory methods. Ethanol caused defined metabolic changes in muscle, including decreased protein, RNA and DNA contents in chronically treated rats. In acute or chronic+acute studies, ethanol suppressed fractional rates of protein synthesis. alpha-Tocopherol supplementation did not ameliorate the effects of either acute, chronic or chronic+acute alcohol on plantaris muscle protein content or rates of protein synthesis. In control animals (not treated with alcohol), alpha-tocopherol supplementation decreased muscle protein content owing to increases in protein turnover (both synthesis and degradation). alpha-Tocopherol supplementation is not protective against the deleterious effects of alcohol on protein metabolism in skeletal muscle.

Potent in vivo antiviral activity of the herpes simplex virus primase-helicase inhibitor BAY 57-1293.

BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model. It is active in parenteral, oral, and topical formulations. BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.